Neuron cell death features prominently in the development of the nervous system and is a key pathological component in neurodegenerative disorders such as Alzheimer's disease (AD). Currently, there is no effective treatment for AD. One view of pathogenesis suggests that neuronal death in development and disease are due to activation of cell death genes and that controlling expression of these genes will make it possible to prevent degeneration. Target-derived neurotrophic factors prevent neuronal death in development; they also act to prevent degeneration induced by lesions of mature neurons. They may prevent cell death in AD. It is our hypothesis that nerve growth factor (NGF) will prevent selective, spontaneous degeneration of basal forebrain cholinergic neurons (BFCN) in a recently developed animal model of AD. The model is based on the finding that all Down syndrome (DS) patients develop AD pathology, including degeneration of BFCN. Mouse trisomy (TS) 16 is an animal model of DS. We have found that TS16 basal forebrain transplants demonstrate atrophy of BFCN after several months in vivo. NGF, or a vehicle control, will be infused into the cerebral ventricle of adult female mice carrying transplanted basal forebrain neurons from TS 16 and control (diploid) fetuses. The number and size of TS16 cholinergic neurons will be compared to controls, and the incidence of extracellular amyloid and neurofibrillary tangles will be assessed. These studies will determine whether or not NGF treatment prevents atrophy and death of BFCN and will give evidence for or against NGF mediated toxicity. If NGF is shown to be both effective and safe, these studies would give strong support to NGF trials in AD patients. The NGF gene family members brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may also act on BFCN; they will be tested for activity on lesioned BFCN and, when appropriate, in the transplant model. To pursue the goal of neurotrophic drug design, we will attempt to define NGF domains important for receptor binding and activation. The strategy to be used is based on the fact that NGF, BDNF and N.T-3 activate distinct populations of neurons. Structural differences between them must lead to activation of distinct receptors. Chimeras in which variant domains from BDNF or NT-3 replace those of NGF will be tested for activity and binding. When activity is changed to that for the factor whose domains were introduced, we will have identified structural regions important for NGF receptor activation. The proposed studies will markedly advance studies of neurotrophic therapy by extending observations to an animal model of the BFCN degeneration. NGF and neurotrophic factors related to NGF may be shown effective and safe in preventing cholinergic cell death. Finally, our studies will pave the way for future neurotrophic design.